LADA MODY GDM.pdf

MONOGENIC DIABETES (MATURITY ONSET DIABETES OF THE YOUNG) LATENT AUTOIMMUNE DIABETES IN ADULTS & GESTATIONAL DIABETES Emily Bodfish, MPAS, PA-C Clinical Assistant Professor Emory and Henry School of Health Sciences  OUTLINE Monogeni...

MONOGENIC DIABETES (MATURITY ONSET DIABETES OF THE YOUNG) LATENT AUTOIMMUNE DIABETES IN ADULTS & GESTATIONAL DIABETES Emily Bodfish, MPAS, PA-C Clinical Assistant Professor Emory and Henry School of Health Sciences  OUTLINE Monogenic diabetes (MODY) Latent Autoimmune Diabetes in Adults Gestation Diabetes DIABETES REVIEW  DIABETES MELLITUS: A GROUP OF METABOLIC DISEASES CHARACTERIZED BY HYPERGLYCEMIA Gestational diabetes Diabetes diagnosed in the 2nd or 3rd trimester of pregnancy mellitus (GDM): without evidence of diabetes prior to pregnancy Maturity-onset Genetic defects of pancreatic B cell function – several diabetes of the types young (MODY): Latent autoimmune Slowly developing Type 1 DM in older adults diabetes in adults Initially have no insulin-dependence & ketoacidosis (LADA): Over time B cells diminish & insulin-dependence develops  DIAGNOSIS What are the 4 ways in which we can diagnose diabetes?  DIABETES PAT H O P H YS I O L O G Y What is the Pathophysiology of Type I Diabetes? Type II Diabetes?  MONOGENIC DIABETES (SUBGROUP: MATURITY ONSET DIABETES OF THE YOUNG) MODY  MATURITY ONSET DIABETES OF THE YOUNG (MODY) Single gene disorders, leading to genetic defects of pancreatic B cell function Non-insulin requiring diabetes The most common form of monogenic diabetes→ 2 to 5% of diabetes Age of onset ≤ 25 years with lack of autoantibodies Autosomal dominant inheritance – multiple gene abnormalities on different chromosomes  MODY 6 types of mutations: Mutations in GCK (glucokinase) & HNF (hepatocyte nuclear factor) genes are most common cause GCK Mutation Causes mild, asymptomatic stable fasting hyperglycemia No treatment required, can be diet controlled, unless pregnant HNF Mutation Cause a progressive pancreatic beta-cell dysfunction and hyperglycemia that can cause microvascular complications. Can be controlled well with a sulfonylurea Copyrights apply  Presentation: Quite heterogeneous May not be reliable in predicting the underlying pathogenesis MODY Generally, patients exhibit mild, stable, fasting hyperglycemia Typically no obesity  MODY Often have one or more of the following features: Strong FH of diabetes of any type (2 Generations) Insulin independence Lack of ketoacidosis when insulin omitted outside 5 years following diagnosis Absence of autoantibodies for pancreatic antigens Evidence of endogenous insulin production Insulin resistance is not a feature of MODY  MODY The presence of autoantibodies makes MODY very unlikely Before Genetic Testing, measure serum autoantibodies Islet Cell Cytoplasmic Autoantibodies (ICA) Glutamic Acid Decarboxylase Autoantibodies (GADA) Insulinoma-Associated-2 Autoantibodies (IA-2A) Insulin Autoantibodies (IAA) Zinc Transporter-8 Autoantibodies (ZnT8A)  MODY DIAGNOSIS Genetic testing by direct sequencing of the gene Genetic testing will allow for: Optimal treatment of patients Identification of family members who are at risk Identify those at risk for diabetes complications which varies with type DIFFERENTIATING MODY FROM TYPE II DM Age of onset 2 generations) Insulin Resistance is not a feature of MODY Diabetes in the absence of obesity is suspicious for MODY, particularly in adolescents Many may go undetected Copyrights apply LATENT AUTOIMMUNE DIABETES OF ADULTS (LADA)  Patients with adult-onset diabetes with circulating autoantibodies directed against pancreatic beta cell antigen They have prolonged preservation of insulin secretion but eventually will LATENT AUTOIMMUNE progress DIABETES OF ADULT Slowly developing type I in (LADA) older adults Considered a slowly progressive variant of type I diabetes Accounts for a small fraction of patients with diabetes  LATENT AUTOIMMUNE DIABETES OF ADULT Despite presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune beta-cell failure is slow These patients do not require insulin initially However, within approximately 6 years, beta cells function is severely impaired & may require insulin Among patients with the phenotypic appearance of DM II - LADA occurs in 10% of those older than 35 years & in 25% Obesity does not exclude LADA Obese DM II pts with islet antibodies show progressive beta-cell failure While initially thought to only affect adults, there have been instances of this disorder in children  Measure autoantibodies when the diagnosis of type 1 or type 2 diabetes is uncertain by clinical presentation: Thin patient with poor response to initial therapy with sulfonylureas LADA or metformin DIAGNOSIS Personal or family history of autoimmune disease Overweight or obese children or adolescents presenting with apparent type 2 diabetes, who in actuality, may have an early presentation of type 1 diabetes  Five of the most common diabetes-related autoantibody tests include: Islet Cell Cytoplasmic Autoantibodies (ICA) Glutamic Acid Decarboxylase L A DA D I AG N O S I S Autoantibodies (GADA) Insulinoma-Associated-2 Autoantibodies (IA-2A) Insulin Autoantibodies (IAA) Zinc Transporter- 8 Autoantibodies (ZnT8A)  Measuring more than one antibody will increase the likelihood of a positive value, but it is costly. Insulin antibodies should not be measured if the patient has received insulin therapy for ≥2 weeks, because this will generate insulin antibodies. If ≤1 antibodies present→ patient should be LADA presumed to have type I diabetes DIAGNOSIS Treated with insulin replacement therapy, as these patients respond poorly to diet & oral hypoglycemic drug therapy. During early stages in the development of type 1 diabetes, intensive insulin therapy prolongs beta cell function  Like that of DM I Obese LADA pts benefit from calorie restriction & physical activity Metformin thought to be useful in LATENT these patients AUTOIMMUNE Insulin therapy is treatment of choice DIABETES OF at diagnosis ADULT Because of the slow progression of TREATMENT β-cell failure, patients with autoimmune diabetes of this type are candidates for immunomodulation  Hormones in pregnancy are associated with insulin resistance Diabetes developing in the second or third trimester of pregnancy in patients not previously diabetic G E STATI ONAL DI AB E T ES Pregnant women are screened between 24 & 28 weeks ~4% of pregnancies affected each year  GESTATIONAL DIABETES IMPLICATIONS Large for gestational age (LGA) infant Defined as fetal or neonatal weight at or above the 90th percentile for gestational age Macrosomia - Defined as birth weight ≥4000 grams Can cause increased maternal & perinatal morbidity Increased risk of operative delivery cesarean or instrumental vaginal Adverse neonatal outcomes→ shoulder dystocia & its associated complications: brachial plexus injury, fracture  GESTATIONAL DIABETES IMPLICATIONS Preeclampsia & gestational hypertension Patients with GDM are at higher risk of developing preeclampsia & gestational hypertension Polyhydramnios – Polyhydramnios is more common in patients with GDM Stillbirth Patients with GDM & suboptimal glucose control appear to have an increased risk of stillbirth compared with the general obstetric population  GESTATIONAL DIABETES COMPLICATIONS Neonatal morbidity Increased risk of hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia, respiratory distress, &/or cardiomyopathy Delayed pulmonary, hepatic, & neurologic organ maturity Congenital defects heart, neural tube, renal Abnormal fetal heart rate patterns Intrauterine fetal growth retardation, & intrauterine fetal distress Maternal Infections Maternal hypoglycemia, diabetic coma, ketoacidosis Maternal cardiac, renal , ophthalmic, & peripheral vascular injuries  Risks extend beyond the pregnancy & neonatal period LONG TERM GDM is a strong marker for CONSEQUENCES maternal development of type 2 OF diabetes, including diabetes-related GESTATIONAL vascular disease. DIABETES GDM increases the offspring's risk for developing obesity, impaired glucose tolerance, & diabetes.  Personal Family hx history of of diabetes, impaired glucose especially tolerance, first-degree RISK FACTORS FOR Hgb A1c>5.7 relatives GESTATIONAL DIABETES Pre-pregnancy BMI >30, weight gain in early adulthood, Older between pregnancies, or maternal between 18 & 24 weeks of age >40 pregnancy  SCREENING FOR GESTATIONAL DIABETES Obtain hemoglobin A1c as part of prenatal laboratory studies at the initial visit Manage as diabetic if >6.5 Targeted screening at 24-28 weeks gestational age with oral 1 hour glucose tolerance test: 50-gram 1-hour oral glucose challenge test (OGCT) without PO intake restriction 1 hour serum glucose > 140 mg/dl = abnormal → 3-hour OGTT 1 hour serum glucose > 200 mg/dl = GDM (3-hour OGTT not performed)  SCREENING FOR GESTATIONAL DIABETES 3-hour OGTT (if screen is abnormal, after overnight fast ) FBS obtained prior to start of test 100 gram oral glucose load ≥ 2 abnormal values = GDM  GESTATIONAL DIABETES MANAGEMENT Team approach: Patient, obstetrician, MFM specialist, nutritionist Goal = Euglycemia: FBS < 95 mg/dl 1 hr PP glucose < 140 mg/dl 2 hr PP glucose < 120 mg/dl  Diet: 30-35 kcal/kg/d 3 small to moderate sized meals with 2 snacks Limit carbohydrates to no more than 40% of diet, with ensuring that ketosis does not develop 40% carbohydrate, 20% protein, 40% fat with generous amount of fiber GESTATIONAL DIABETES MANAGEMENT Exercise: Encourage mild to moderate aerobic exercise (walking) after meals Prevent gestational weight gain Glucose Monitoring: Fasting & 1-2 hours post prandial At least a total of 4 times a day  Medication: For patients not getting adequate control with diet and exercise Insulin is the medication of choice: Preferred = Combination of short acting G E STATI ONAL (lispro or aspart) pre-meal & intermediate DI AB E T ES T R E ATMENT acting (NPH) insulin Basal insulin (glargine & detemir) have not been studied extensively but appear safe 2nd line/alternatives Metformin: Initial 500 mg daily or bid, max 2-2.5 g daily in two divided doses Glyburide 2.5-5 mg PO daily, increase 2.5 mg/wk. PRN to Max. 20 mg/day Both drugs cross the placenta (in contrast to insulin)  INSULIN THERAPY IN GESTATIONAL DIABETES Starting Insulin Dose 0.7-1.0 U/kg/d (based on present pregnant weight) Combination of Intermediate & short acting insulin 2/3 of the Insulin dose given in the morning before breakfast Morning dose: 2/3 NPH, 1/3 regular 1/3 total daily dose is given in the evening before dinner ½ is regular ½ is NPH  CALCULATION What is the insulin regimen for a 30-week gestational age 36-year-old OB patient with gestational diabetes who weighs 165 pounds (using the lower starting dose of 0.7 u/kg/d)  Antepartum: Detailed ultrasonic study of fetus including echocardiogram to screen for fetal congenital heart malformations DIABETES Serial biophysical profile (BPP) weekly MANAGEMENT beginning at 32-34 wks GA IN Delivery: PREGNANCY Spontaneous labor & vaginal delivery at term preferred if fetus stable Cesarean delivery may be elected for large fetuses (>4500 g = 10 lbs)  Intrapartum: Glucose control: Monitor maternal glucose levels every hour Maintain maternal euglycemia during DIABETES labor (80-120 mg/dl) MANAGEMENT IN Continuous infusion (IV) or PRN SQ PREGNANCY doses of regular insulin are given for ↑glucose Fetal monitoring: Continuous electronic FHR monitoring is recommended for all DM patients  DIABETES MANAGEMENT IN PREGNANCY Postpartum: After delivery of fetus & placenta insulin requirements drop sharply Monitor plasma glucose levels QID (FBS & 1 hr postprandial) Treat elevated glucose levels with lispro or regular insulin PRN Screen for Type II DM 6 weeks postpartum with 2hr OGTT GDM patients should be counseled on use of ADA diet Estrogen containing OCPs are not recommended for DM with vascular disease